INDO-US Collaboration to Develop Rotavirus Vaccines

轮状病毒感染所有5岁以下的儿童，是全球严重胃肠炎的最常见原因。在美国，轮状病毒是一种常见的致病原因，占相当大的医疗保健成本。然而，发病率和死亡率在发展中国家最为严重。疾病负担研究已经确定轮状病毒是印度儿童腹泻和死亡的重要原因。在印度，轮状病毒是造成大约20%腹泻的原因 相关住院和100，000例死亡;每年因轮状病毒而住院的人数约为500，000。首次轮状病毒感染与最严重的腹泻有关，但天然免疫力可防止再次感染后的严重腹泻。口服活疫苗可预防婴儿严重轮状病毒腹泻，并且已经开发了几种轮状病毒疫苗。迄今为止，唯一获得许可的轮状病毒疫苗--一种口服、活的、四价的、以恒河猴为基础的疫苗--在临床试验中被发现是安全有效的。然而，由于疫苗接种者中肠套叠的发病率增加，它随后从美国市场撤出。仍然需要轮状病毒疫苗计划来预防轮状病毒相关的发病率和死亡率的全球负担。这是发展中国家的一个高度优先事项，导致对其他疫苗的研究。该研究将研究两种口服轮状病毒候选活疫苗，116 E和I321株，用于预防印度儿童严重轮状病毒腹泻。疫苗株的开发是基于分子和流行病学证据，即它们是天然存在的人牛免疫原，在印度流行，具有良好的临床和免疫学特征。每种印度菌株在基因型上都是不同的，如果不进行拟定的临床试验，就无法确定哪种菌株的优效性。这两种疫苗都将进行平行测试，以确定最可行的候选疫苗（例如，较高的致突变性、较差的免疫原性、较低的效力、较低的产量）。AIIMS（印度）、IISc（印度）、斯坦福大学和CDC的研究人员建议开展合作，在印度婴儿中开展印度菌株的I、II和[II]期临床研究。这一合作将为疫苗测试和评价提供能力建设 在AIIMS中心。通过这种合作，也有机会了解与肠套叠发病机制相关的宿主和病原体相关因素。拟议的研究将支持印度未来的疫苗开发工作，以及了解与口服活疫苗相关的不良事件。

Rotavirus infects all children by 5 years of life, and is the most common cause of severe gastroenteritis worldwide. In the US, rotavirus is a common cause of morbidity, accounting for considerable health-care costs. However, morbidity and mortality are most serious in developing countries. Disease burden studies have established rotavirus as an important cause of diarrhea and death in Indian children. In India, rotavirus is responsible for about 20% of diarrhea related hospitalizations and 100,000 deaths; the annual number ofrotavirus specific hospitalizations is approximately 500,000. First rotavirus infections are associated with the most severe diarrhea, but natural immunity protects against severe diarrhea upon reinfection. Live, oral vaccines protect against severe rotavirus diarrhea of infancy, and several rotavirus vaccines have been developed. The only rotavirus vaccine licensed to date - an oral, live, tetravalent, rhesus-based vaccine -was found to be safe and efficacious in clinical trials. However, it was subsequently withdrawn from the US market because of an increased incidence of intussusception among vaccine recipients. A rotavirus vaccine program is still needed to prevent the global burden of rotavirus associated morbidity and mortality. This is a high priority in developing countries leading to investigation of other vaccines. The proposed study will investigate two live, oral rotavirus candidate vaccines, strains 116E and I321, for prevention of severe rotavirus diarrhea in Indian children. Development of the vaccine strains is based on molecular and epidemiologic evidence that they are naturally occurring human bovine reassortants, circulating in India, with favorable clinical and immunologic profiles. Each of the Indian strains is genotypically distinct and there is no way to determine to superiority of either without conducting the proposed clinical trials. Both will be tested in parallel to define the most viable vaccine candidate (e.g., higher cactogenicity, poor immunogenicity, low efficacy, low yield). Collaborative efforts by investigators at AIIMS (India), IISc (India), Stanford University and CDC are proposed to conduct Phase I, II and [II clinical studies of the Indian strains among Indian infants. This collaboration will provide capacity-building for a vaccine testing and evaluation center at AIIMS. The opportunity to understand host and pathogen-associated factors related to pathogenesis of intussusception is also available through this collaboration. The proposed studies will support future efforts towards vaccine development in India as well as to understanding of adverse events associated with live, oral vaccines.